Apparatus and formulations for suprachoroidal drug delivery

ABSTRACT

Drug formulations, devices and methods are provided to deliver biologically active substances to the eye. The formulations are delivered into scleral tissues adjacent to or into the suprachoroidal space without damage to the underlying choroid. One class of formulations is provided wherein the formulation is localized in the suprachoroidal space near the region into which it is administered. Another class of formulations is provided wherein the formulation can migrate to another region of the suprachoroidal space, thus allowing an injection in the anterior region of the eye in order to treat the posterior region.

CROSS-REFERENCE TO RELATED APPLICATION

This is a division of US Ser. No. 11/709,941, filed Feb. 21, 2007,which, in turn, claims the priority of provisional U.S. Ser. No.60/776,903, filed Feb. 22, 2006, pursuant to 35 USC 119(e). The priorapplications are incorporated herein by reference in their entirety forall purposes.

FIELD OF THE INVENTION

The invention relates to the field of drug delivery into the eye.

BACKGROUND OF INVENTION

The eye is a complex organ with a variety of specialized tissues thatprovide the optical and neurological processes for vision. Accessing theeye for medical treatment is hindered by the small size and delicatenature of the tissues. The posterior region of the eye, including theretina, macula and optic nerve, is especially difficult to access due tothe recessed position of the eye within the orbital cavity. In addition,topical eye drops penetrate poorly into the posterior region, furtherrestricting treatment options.

The suprachoroidal space is a potential space in the eye that is locatedbetween the choroid, which is the inner vascular tunic, and the sclera,the outer layer of the eye. The suprachoroidal space extends from theanterior portion of the eye near the ciliary body to the posterior endof the eye near the optic nerve. Normally the suprachoroidal space isnot evident due to the close apposition of the choroid to the sclerafrom the intraocular pressure of the eye. Since there is no substantialattachment of the choroid to the sclera, the tissues separate to formthe suprachoroidal space when fluid accumulation or other conditionsoccur. The suprachoroidal space provides a potential route of accessfrom the anterior region of the eye to treat the posterior region.

The present invention is directed to drug formulations foradministration to the suprachoroidal space and an apparatus to deliverdrugs and other substances in minimally invasive fashion to thesuprachoroidal space.

SUMMARY

Drug formulations are provided characterized by a zero shear viscosityof at least 300,000 mPas. A subclass of the drug formulations is furthercharacterized by a viscosity of not more than about 400 mPas at 1000 s⁻¹shear rate.

For injection into the suprachoroidal space of an eye comprising abiologically active substance and a thixotropic polymeric excipient thatacts as a gel-like material to spread after injection and uniformlydistribute and localize the drug in a region of the suprachoroidalspace. In one embodiment, gel-like material crosslinks after injectioninto the suprachoroidal space. The biologically active substance maycomprise microparticles or microspheres. The polymeric excipient maycomprise hyaluronic acid, chondroitin sulfate, gelatin,polyhydroxyethylmethacrylate, dermatin sulfate, polyethylene oxide,polyethylene glycol, polypropylene oxide, polypropylene glycol,alginate, starch derivatives, a water soluble chitin derivative, a watersoluble cellulose derivative or polyvinylpyrollidone.

In another embodiment, a drug formulation is provided for delivery tothe suprachoroidal space of an eye comprising a biologically activesubstance and microspheres with an outer diameter in the range of about1 to 33 microns. The microparticles or microspheres additionally maycomprise a controlled release coating and/or a tissue affinity surface.

The biologically active substance preferably comprises an antibiotic, asteroid, a non-steroidal anti-inflammatory agent, a neuroprotectant, ananti-VEGF agent, or a neovascularization suppressant.

Devices are also provided for minimally invasive delivery of a drugformulation into the suprachoroidal space of the eye comprising a needlehaving a leading tip shaped to allow passage through scleral tissueswithout damage to the underlying choroidal tissues, and a sensor toguide placement of the tip to deliver the formulation adjacent to orwithin the suprachoroidal space.

The sensor may provide an image of the scleral tissues. The sensorpreferably responds to ultrasound, light, or differential pressure.

In another embodiment, devices are provided for minimally invasivedelivery of a drug formulation into the suprachoroidal space of the eyecomprising a needle having a leading tip shaped to allow passage throughscleral tissues, and an inner tip that provides an inward distendingaction to the choroid upon contacting the choroid to prevent traumathereto.

Methods are provided for administering drugs to the eye comprisingplacing a formulation comprising a biologically active substance and apolymer excipient in the suprachoroidal space such that the excipientgels after delivery to localize said biologically active substance. Theformulation may be placed in a posterior or anterior region of thesuprachoroidal space.

In another embodiment, method are provided for administering drugs to aposterior region of the eye comprising placing a formulation comprisinga biologically active substance comprising microspheres ormicroparticles with an outer diameter in the range of about 1 to 33microns in an anterior region of the suprachoroidal space such that themicrospheres or microparticles subsequently migrate to the posteriorregion. The formulation preferably comprises a polymer excipient touniformly disperse the microparticles or microspheres in thesuprachoroidal space.

In another embodiment, a method is provided of administering drugs inthe suprachoroidal space of the eye comprising the steps of placing aneedle in scleral tissues toward the suprachoroidal space at a depth ofat least half of the scleral thickness, and injecting a drug formulationthrough the needle into the sclera such that the formulation dissectsthe scleral tissues adjacent to the suprachoroidal space and enters thesuprachoroidal space.

In the methods disclosed herein, the formulation preferably comprises athixotropic polymer.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an ultrasound image of a portion of the eye after injection byneedle into the sclera of a hyaluronic acid surgical viscoelasticmaterial according to Example 9.

FIG. 2 is an ultrasonic image of a portion of the eye during injectionby needle into the sclera of a 1:1 by volume mixture of the viscoelasticmaterial and 1% solution of polystyrene microspheres according toExample 9.

FIGS. 3a and 3b are diagrams of an embodiment of a delivery deviceaccording to the invention having a distending and cutting or ablativetip.

FIG. 4 is a diagram showing the location of a delivery device accordingto the invention relative to the target sclera, suprachoroidal space andchoroid.

FIG. 5 is a diagram of an embodiment of a delivery device according tothe invention having a stop plate to set the depth and angle ofpenetration of the needle into the eye.

FIG. 6 is a diagram of an embodiment of a delivery device according tothe invention that accommodates a microendoscope and camera to monitorthe location of the cannula tip during surgery.

FIG. 7 is a diagram of an embodiment of a delivery device having a lumenfor delivery of drugs through a catheter into the eye and a fiber opticline connected to an illumination source to illuminate the tip if thecannula.

FIG. 8 is a diagram of an embodiment of the use of a device according tothe invention in conjunction with a high resolution imaging device tomonitor the location of the tip of the cannula.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention comprises drug formulations, devices and relatedmethods to access the suprachoroidal space of an eye for the purpose ofdelivering drugs to treat the eye. Specifically, the invention relatesto drug formulations designed for suprachoroidal space administration totreat the eye, including specific regions of the eye by localization ofthe delivered drug. The invention also relates to the design and methodsof use for a minimally invasive device to inject drug formulations anddrug containing materials directly into the suprachoroidal space througha small needle.

A biologically active substance or material is a drug or other substancethat affects living organisms or biological processes, including use inthe diagnosis, cure, mitigation, treatment, or prevention of disease oruse to affect the structure or any function of the body. A drugformulation contains a biologically active substance.

As used herein, the anterior region of the eye is that region of the eyethat is generally readily accessible from the exposed front surface ofthe eye in its socket. The posterior region of the eye is generally theremaining region of the eye that is primarily surgically accessedthrough a surface of the eye that is unexposed, thus often requiringtemporary retraction of the eye to gain access to that surface.

Formulations:

The drug formulations of the invention provide compatibility with thesuprachoroidal space environment and may be formulated to control thedistribution of the biologically active substance by migration of theformulation as well as provide for sustained release over time. The drugformulation comprises one or more biologically active substancesformulated with physiologically compatible excipients that areadministered, typically by injection, into the suprachoroidal space ofan eye. Suitable biologically active substances include antibiotics totreat infection, steroids and non-steroidal anti-inflammatory compoundsto treat inflammation and edema, neuroprotectant agents such as calciumchannel blockers to treat the optic nerve and retinal agents such asanti-VEGF compounds or neo-vascular suppressants to treat maculardegeneration.

Formulations for Localized Treatment:

For treatment of a localized region of the eye, for example, to treat amacular lesion, the posterior retina, or the optic nerve, the drug maybe prepared in a formulation to limit migration after delivery anddelivered to the region of the lesion. While not intending to be boundby a particular theory, we observe that drug microparticles typicallytravel toward the posterior region of the suprachoroidal space underphysiological conditions, presumably due to uveal-scleral fluid flowwithin the space. Such drug microparticles may be fabricated withsufficient size and optionally with tissue surface affinity to limitdrug migration. Tissue surface affinity may be modified by the additionof polymeric or lipid surface coatings to the microparticles, or by theaddition of chemical or biological moieties to the microparticlesurface. Tissue affinity is thereby obtained from surface charge,hydrophobicity, or biological targeting agents such as antibodies orintegrins that may be incorporated to the surface of the microparticlesto provide a binding property with the tissues to limit drug migration.Alternatively or in combination, the drug may be formulated with one ormore polymeric excipients to limit drug migration. A polymeric excipientmay be selected and formulated to act as a viscous gel-like materialin-situ and thereby spread into a region of the suprachoroidal space anduniformly distribute and retain the drug. The polymer excipient may beselected and formulated to provide the appropriate viscosity, flow anddissolution properties. For example, carboxymethylcellulose is a weaklythixotropic water soluble polymer that may be formulated to anappropriate viscosity at zero shear rate to form a gel-like material inthe suprachoroidal space. The thixotropic effect of the polymer may beenhanced by appropriate chemical modification to the polymer to increaseassociative properties such as the addition of hydrophobic moieties, theselection of higher molecular weight polymer or by formulation withappropriate surfactants. Preferred is the use of highly associativepolymeric excipients with strong thixotropic properties such ashyaluronic acid to maximize the localization and drug retainingproperties of the drug formulation while al lowing the formulation to beinjected through a small gauge needle. The dissolution properties of thedrug formulation may be adjusted by tailoring of the water solubility,molecular weight, and concentration of the polymeric excipient in therange of appropriate thixotropic properties to allow both deliverythrough a small gauge needle and localization in the suprachoroidalspace. The polymeric excipient may be formulated to increase inviscosity or to cross-link after delivery to further limit migration ordissolution of the material and incorporated drug. For example, a highlythixotropic drug formulation will have a low viscosity during injectionthrough a small gauge needle, but dramatically increases in effectiveviscosity once in the suprachoroidal space at zero shear conditions.Hyaluronic acid, a strongly thixotropic natural polymer, when formulatedat concentrations of 1 to 2 weight percent demonstrates a viscosity ofapproximately 300,000 to 7,000,000 mPas at zero shear and viscosity of150 to 400 mPas at a shear rate of 1000 s, typical of injection though asmall gauge needle, with the exact viscosity depending of the molecularweight. Chemical methods to increase the molecular weight or degree ofcrosslinking of the polymer excipient may also be used to increaselocalization of the drug formulation in-situ, for example theformulation of hyaluronic acid with bisepoxide or divinylsulfonecrosslinking agents. The environment in the suprachoroidal space mayalso be used to initiate an increase in viscosity or cross-linking ofthe polymer excipient, for example from the physiologic temperature, pHor ions associated with the suprachoroidal space. The gel-like materialmay also be formulated with surface charge, hydrophobicity or specifictissue affinity to limit migration within the suprachoroidal space.

Water soluble polymers that are physiologically compatible are suitablefor use as polymeric excipients according to the invention includesynthetic polymers such as polyvinylalcohol, polyvinylpyrollidone,polyethylene glycol, polyethylene oxide, polyhydroxyethylmethacrylate,polypropylene glycol and propylene oxide, and biological polymers suchas cellulose derivatives, chitin derivatives, alginate, gelatin, starchderivatives, hyaluronic acid, chondroiten sulfate, dermatin sulfate, andother glycosoaminoglycans, and mixtures or copolymers of such polymers.The polymeric excipient is selected to allow dissolution over time, withthe rate controlled by the concentration, molecular weight, watersolubility, crosslinking, enzyme lability and tissue adhesive propertiesof the polymer. Especially advantageous are polymer excipients thatconfer the formulation strong thixotropic properties to enable the drugformulation to exhibit a low viscosity at high shear rates typical ofdelivery through a small gauge needle to facilitate administration, butexhibit a high viscosity at zero shear to localize the drug in-situ.

To treat an anterior region of the eye, a polymeric excipient to limitdrug migration may be combined with a drug and injected into the desiredanterior region of the suprachoroidal space.

One method for treating the posterior region of the eye comprisesadministration of a drug formulation with localizing properties directlyto the posterior region of the suprachoroidal space. Drug formulationsmay be delivered to the posterior region of the suprachoroidal space byusing a flexible microcannula placed in an anterior region of thesuprachoroidal space with subsequent advancement of the distal tip tothe posterior region prior to delivery of the drug and a localizingexcipient. Similarly, a flexible microcannula may be advanced to thecenter of a desired treatment area such as a macular lesion prior todelivery of a drug formulation with properties to localize theadministered drug.

Treatment of a localized region of the eye, especially the posteriorregion, is facilitated by the use of drug preparations of the presentinvention in combination with administration devices to deliver thepreparation locally to various regions of the suprachoroidal space witha flexible device as described in U.S. patent application 60/566,776 bythe common inventors, incorporated by reference herein in its entirety.

Formulations for Migration to a Posterior Region:

For treatment of the posterior region of the eye, for example, to treatthe entire macula, choroid or the optic nerve, the drug may be preparedin a form to allow migration after delivery and delivered to an anteriorregion of the suprachoroidal space. The drug may be formulated insoluble form, with a rapid dissoluting polymeric excipient or as smallmicroparticles or microspheres to allow drug migration afteradministration. If a polymeric excipient is used, a low viscosity,rapidly absorbed formulation may be selected to distribute the druguniformly in the region of administration to minimize areas of overlyhigh drug concentration, and subsequently dissolution of the excipientto allow drug migration to the posterior region of the suprachoroidalspace. Of particular utility is the use of such a polymeric excipient incombination with drug microparticles or microspheres. Such use of drugmigration is advantageous as the drug may be injected into an anteriorregion of the eye easily accessible by the physician, and used to treata posterior region distant from the injection site such as, theposterior choroid and macula. Preferred microparticles or microspheresare those with an outer diameter in the range of about 1 to 33 microns.

Sustained Release:

The use of drug microparticles, one or more polymeric excipients or acombination of both, may also be applied to confer sustained releaseproperties to the drug formulation. The drug release rate from themicroparticles may be tailored by adjusting drug solubility orapplication of a controlled release coating. The polymeric excipient mayalso provide sustained release from incorporated drugs. The polymericexcipient may, for example, be selected to limit drug diffusion orprovide drug affinity to slow drug release. The dissolution rate of thepolymeric excipient may also be adjusted to control the kinetics of itseffect on sustained release properties.

Delivery Devices:

A device for minimally invasive delivery of drugs to the suprachoroidalspace may comprise a needle for injection of drugs or drug containingmaterials directly to the suprachoroidal space. The device may alsocomprise elements to advance the needle through the conjunctiva andsclera tissues to or just adjacent to the suprachoroidal space withoutperforation or trauma to the inner choroid layer. The position of theleading tip of the delivery device may be confirmed by non-invasiveimaging such as ultrasound or optical coherence tomography, externaldepth markers or stops on the tissue-contacting portion of the device,depth or location sensors incorporated into the device or a combinationof such sensors. For example, the delivery device may incorporate asensor at the leading tip such as a light pipe or ultrasound sensor todetermining depth and the location of the choroid or a pressuretransducer to determine a change in local fluid pressure from enteringthe suprachoroidal space.

The leading tip of the delivery device is preferably shaped tofacilitate penetration of the sclera, either by cutting, bluntdissection or a combination of cutting and blunt dissection. Features ofthe device may include energy delivery elements to aid tissuepenetration such as ultrasound, high fluid pressure, or tissue ablativeenergy at the distal tip. The outer diameter of the tissue contactingportion of the device is preferably about the size of a 20 to 25 gaugeneedle (nominal 0.0358 to 0.0203 inch outer diameter) to allow minimallyinvasive use without requiring additional features for tissue dissectionor wound closure. Suitable materials for the delivery device includehigh modulus materials such as metals including stainless steel,tungsten and nickel titanium alloys, and structural polymers such asnylon, polyethylene, polypropylene, polyimide and polyetheretherketone,and ceramics. The tissue contacting portions of the device may alsocomprise surface treatments such as lubricious coatings to assist intissue penetration or energy reflective or absorptive coatings to aid inlocation and guidance during medical imaging.

The needle may be mounted or slidably disposed at a shallow angle to aplate or fixation mechanism to provide for localization and control ofthe angle and depth of insertion. The plate, such as shown in FIG. 4,may contain an injection port to allow advancement of the needle throughthe plate that has been pre-positioned on the surface of the globe (eyesurface). The plate may further comprise a vacuum assist seal 12 toprovide stabilization of the plate to the target site on the ocularsurface. An external vacuum source such as a syringe or vacuum pump isconnected by line 13 to the plate to provide suction. The plate shouldpreferably have a bottom side or bottom flanges which are curvedsuitably to curvature of the globe. The needle 11 is advanced throughthe sclera 1 until entering the suprachoroidal space 2 but not intochoroid 3.

Elements to seal the needle tract during injection such as a flexibleflange or vacuum seal along the tract may also be incorporated to aiddelivery. Referring to FIG. 4, the location of the delivery device 11 isshown with respect to the target sclera 1, suprachoroidal space 2, andchoroid 3 by positioning with a vacuum interfacial seal 12 attached to asuction line 13.

The device may also comprise elements to mechanically open thesuprachoroidal space, in order to allow injection of microparticulatedrugs or drug delivery implants which are larger than can be deliveredwith a small bore needle. In one embodiment, such a delivery device maycomprise a first element provided to penetrate the scleral tissue to aspecified depth, and a second element, which can advance, andatraumatically distend the choroid inwards, maintaining a pathway to thesuprachoroidal space. The second element may be disposed within orplaced adjacent to the first element. An embodiment of a device havingsuch elements is shown in FIGS. 3a and 3 b.

Referring to FIG. 3a a delivery device with a distending tip is shown.The delivery device comprises a cutting or ablative tip 4 a choroidaldistention tip 8 at the distal end of the device, and an ultrasonicsensor 6 used to guide the device through the tissues. A luer connector7 is provided at the proximal end (away from the cutting tip) of thedevice. The knob 5 is connected to the mechanism for activating thedistention tip 8. The device is placed facing the sclera 1 to addressthe suprachoroidal space 2 adjacent to the choroid 3. The device is thenadvanced in scleral tissues using the depth sensor for guidance. Whenthe depth sensor indicates that the tip 4 is to or just adjacent to thesuprachoroidal space 2, the distension tip 8 is activated to preventdamage to the choroid. Referring to FIG. 3b , the knob 5 has beenactivated to advance the distention tip to its activated position 9which results in a distended choroid 10. A pathway to the suprachoroidalspace 2 is thereby attained without trauma to the choroid from theablative tip 4.

In another embodiment, the delivery device comprises a thin walledneedle fabricated with a short, high angle bevel at the leading tip toallow the bevel to be advanced into or through scleral tissues.Maintaining the beveled section with the opening directed inwardprevents the drug from being expressed away from the suprachoroidalspace. Various types of access and delivery may be achieved through theprecise placement of the needle tip into or through the scleral tissues.If the needle is advanced through the sclera and into the suprachoroidalspace, the needle may then be used for direct injections into the spaceor to serve as an introducer for the placement of other devices such asa microcannula. If the needle is placed in close proximity to the innerboundary of the sclera, injection of drug formulations through theneedle will allow fluid dissection or flow through any remaininginterposing scleral tissue and delivery to the suprachoroidal space. Anembodiment of a device useful in such manner is shown in FIG. 8.

In FIG. 8, a system to inject a substance into the suprachoroidal space2 comprises an access cannula 26 and a high resolution imaging device27. The access cannula may accommodate a hypodermic type needle (notshown) or introducer sheath with a trocar (not shown). Furthermore, theaccess means may comprise a plate as shown in FIG. 4 or FIG. 5. Theaccess cannula incorporates a beveled sharp distal tip suitably shapedfor penetration of the tissues. The imaging device may comprisereal-time modalities such as ultrasound, optical coherence tomography(OCT) or micro-computed tomography (MicroCT). The advancement of theaccess needle or introducer through the sclera is monitored using theimaging device. The access cannula 26 is advanced until the leading tipis in close proximity to the inner boundary of the sclera 28, at whichpoint the injection of the drug is made. Injection of drug formulationsthrough the needle will allow fluid dissection or flow through anyremaining interposing scleral tissue and delivery to the suprachoroidalspace 29.

In one embodiment, the delivery device may allow a specific angle ofentry into the tissues in order to provide a tissue pathway that willmaintain the tract within the sclera, or penetrate to the suprachoroidalspace without contacting the choroid. Referring to FIG. 5, an embodimentof the device is shown with a luer connector 7 at the proximal end and abevel needle tip 14 at the distal end. The needle is affixed to anangled stop plate 15 to set the depth and angle of penetration of theneedle tip 14. The assembly is advanced until the stop plate encountersthe surface of the globe, placing the needle tip at the target depth.The mounting plate may also contain sensors for indicating or directingthe position of the needle tip.

In one embodiment, a system for obtaining minimally invasive access tothe suprachoroidal space comprises an access cannula and an opticaldevice used to determine the location of the access cannula distal tipin the tissue tract providing direct feedback upon entry to thesuprachoroidal space. The color differential between the sclera (white)and the choroid (brown) may be used to provide location information orOCT methods may be used to determine the distance to the choroidinterface from the sclera. The optical device may be incorporated withina microcannula, or may be an independent device such as a microendoscopeor a fiber-optic sensor and transducer capable of detecting the tissueproperties. The optical signal may be sent to a camera and monitor fordirect visualization, as in the case of an endoscope, or to an opticalsignal processing system, which will indicate depth by signaling thechange in tissue properties at the tip of the optical fiber. The accessmicrocannula may be a needle or introducer-type device made of metal orplastic. The distal end of the access cannula is suitable to pierceocular tissue. If independent, the optical device will be removed fromthe access microcannula after cannulation to allow access to the spacefor other devices or for an injectate to administer treatment. Anembodiment of such a system is shown in FIG. 6. The optical devicecomprises a flexible microendoscope 18, coupled to a CCD camera 16 withthe image viewed on a monitor 19. The endoscope is sized to fit slidablyin an access cannula 17 that is preferably less than 1 mm in outerdiameter. The access cannula 17 comprises a beveled sharp distal tip fortissue access. The distal tip of the endoscope is positioned at theproximal end of the cannula bevel to provide an image of the cannulatip. The cannula is advanced against the ocular surface at the region ofthe pars plana at a low angle, piercing the sclera 1, and advancinguntil the endoscope image shows access into the suprachoridal space 2.

In another embodiment, the optical device of the system comprises afocal illumination source at the distal tip. The amount of light scatterand the intensity of the light will vary depending upon the type oftissues and depth of a small light spot traversing the tissues. Thechange may be seen from the surface by the observing physician ormeasured with a sensor. The focal spot may be incorporated as anilluminated beacon tip on a microcannula. Referring to FIG. 7, theaccess device comprises a flexible microcannula or microcatheter 20,sized suitably for atraumatic access into the suprachoroidal space 2.The microcatheter comprises a lumen 22 for the delivery of materials tothe space 2 and a fiber optic 23 to provide for an illuminated distaltip. The fiber optic is connected to an illumination source 24 such as alaser diode, superbright LED, incandescent or similar source. Themicrocatheter is slidably disposed within the access cannula 21. As theaccess cannula is advanced through the tissues, the light 25transilluminating the tissues will change. Scleral tissues scatter lightfrom within the sclera tissues to a high degree, however once inside thesuprachoroidal space, the light intensity and backscatter seen at thesurface diminishes significantly, indicating that the illuminated tiphas transited the sclera 1, and is now in the target location at thesuprachoroidal space.

Of particular utility with a delivery device are drug formulations aspreviously described that are compatible with the delivery device. Drugin microparticulate form are preferred to be substantially smaller thanthe lumen diameter to prevent lumen obstruction during delivery.Microparticles of average outer dimension of approximately 10 to 20% ofthe device lumen at maximum are preferred. A useful formulation includesmicrospheres or microparticles with an outer diameter in the range ofabout 1 to 33 microns. Also preferred is the use of a polymericexcipient in the drug formulation to enable the formulation to beinjected into the scleral tissues adjacent to the suprachoroidal space,with subsequent dissection of the tissue between the distal tip and thesuprachoroidal space by the excipient containing fluid to form a flowpath for the drug into the suprachoroidal space. Formulations withthixotropic properties are advantageous for passage through a smallneedle lumen as well as for fluid dissection of scleral tissue.

The following examples are provided only for illustrative purposes andare not intended to limit the invention in any way.

Example 1

Fluorescent dyed polystyrene microspheres (Firefli™, Duke Scientific,Inc., Palo Alto, Calif.) suspended in phosphate-buffered saline wereused as model drug to evaluate the size range in which particulates willmigrate in the suprachoroidal space from the anterior region to theposterior region.

An enucleated human cadaver eye was radially incised to the choroid inthe pars plana region, which is in the anterior portion of the eye.Using a syringe terminated with a blunt 27 gauge needle, 0.15 mL of a 1%by volume microsphere suspension (mean diameter 6 micron) was deliveredinto the anterior region of the suprachoroidal space. The needle waswithdrawn and the incision sealed with cyanoacrylate adhesive.

The eye was then perfused for 24 hours with phosphate buffered saline at10 mm Hg pressure by introducing into the anterior chamber a 30 gaugeneedle attached to a reservoir via infusion tubing. The reservoir wasplaced on a lab jack and elevated to provide constant perfusionpressure. Several hours prior to examination, the eye was placed into abeaker of glycerin to clarify the scleral tissue by dehydration,allowing direct visualization of the suprachoroidal space.

The microspheres were visualized using a stereofluorescence microscope(Model MZ-16, Leica, Inc.) with fluorescence filters selected for themicrosphere fluorescence. Under low magnification (7 to 35×) themicrospheres could be clearly seen in a stream-like pattern running fromthe site of instillation back toward the optic nerve region, collectingprimarily in the posterior region of the suprachoroidal space.

The experiment was repeated using microsphere suspensions of 1, 6, 10,15, 24 and 33 micron diameter with the same resulting pattern ofmigration and distribution to the posterior region of the eye.

Example 2

The experiment of Example 1 was repeated, except that a mixture of 6 and33 micron diameter fluorescent microspheres as a model drug wassuspended in a polymeric excipient comprising a surgical viscoelastic(Healon 5, Advanced Medical Optics, Inc.), a 2.3% concentration ofsodium hyaluronic acid of 4,000,000 Daltons molecular weight, withthixotropic properties of a zero shear viscosity of 7,000,000 mPas and400 mPas viscosity at 1000 s⁻¹ shear rate. The mixture was introducedinto the suprachoroidal space in the manner of Example 1. After 24 hourperfusion, the microspheres resided solely in the suprachoroidal spaceat the anterior instillation site and did not show evidence ofmigration, demonstrating the localizing effect of the thixotropicpolymeric excipient.

Example 3

To demonstrate the effect of polymeric excipient viscosity on druglocalization, the experiment of Example 1 was repeated, except thatbevacizumab (Avastin™, Genentech), an anti-VEG antibody, was adsorbedonto 5 micron diameter carboxylated fluorescent microspheres and mixedat equal volumes with one of three hyaluronic acid based surgicalviscoelastics (Healon, Healon GV, Healon 5, Advanced Medical Optics,Inc.), each with a different viscosity and thixotropic properties.(Healon, 300,000 mPas viscoscity at zero shear rate, 150 mPas viscosityat 1000 s-1 shear rate; Healon GV, 3,000,000 mPas viscosity at zeroshear rate, 200 mPas at 1000 s-1 shear rate; Healon 5, 7,000,000 mPasviscosity at zero shear rate, 400 mPas viscosity at 1000 s-1 shearrate.) Each mixture was introduced into the anterior region of thesuprachoroidal space at the pars plana in the anterior region of the eyein the manner of Example 1. After 24 hours perfusion, the microspheresin Hcalon and Hcalon GV were found to be in process of migration to theposterior region of the suprachoroidal space with the formulation foundat both the pars plana site of instillation and the posterior pole. Themicrospheres in Healon 5 remained dispersed in the viscoelasticlocalized at the original injection site in the pars plana region of thesuprachoroidal space.

Example 4

The experiment of Example 1 was repeated, except that bevacizumab(Avastin™, Genentech) was covalently crosslinked using1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (EDAC, Sigma-Aldrich)onto 5 micron diameter carboxylated fluorescent microspheres and mixedat equal volumes with one of three surgical viscoelastics (Healon,Healon GV, Healon 5, Advanced Medical Optics, Inc.), each with adifferent viscosity and thixotropic properties as in Example 3. Themixture was introduced into the suprachoroidal space at the pars planain the manner of Example 1. After 24 hour perfusion the microspheresremained exclusively in the pars plana region of the suprachoroidalspace for all viscoelastic carriers.

Example 5

To demonstrate the effect of a crosslinking polymeric excipient on druglocalization, the experiment of Example 1 was repeated, except that 10micron diameter fluorescent microspheres were mixed into a 4% alginatesolution and introduced into the suprachoroidal space at the pars planaregion. Before sealing the incision site an equal volume of 1 M CaCl2solution was instilled at the site of the microsphere/alginatesuspension to initiate crosslinking of the alginate excipient. Themixture was allowed to gel for 5 minutes before perfusing as inExample 1. The microspheres remained exclusively at the site ofinstillation, dispersed in the crosslinked polymer excipient.

Example 6

A drug containing injectate was prepared by suspending 1.5 mg ofTriamcinolone acetonide in microparticulate form, in 15 microliters ofHealon viscoclastic (Advanced Medical Optics, Irvine Calif.) with a zeroshear viscosity of 300,000 mPas and a viscosity of 150 mPas at a shearrate of 1000 s-1. Forty porcine subjects were placed under anesthesiaand the right eye prepared and draped in a sterile manner. Aconjunctival peritomy was made near the superior limbus, exposing andproviding surgical access to a region of sclera. A small radial incisionwas made in the sclera, exposing bare choroid. A flexible microcannulawith a 360 micron diameter tip and 325 micron diameter body (iTrackmicrocannula, iScience Interventional Corp.) was inserted in to thescleral incision and advanced in a posterior direction to a targetregion behind the macula. The drug suspension was injected into theposterior region of the suprachoroidal space, and was observed to form alayer between the choroid and sclera at the target region. Themicrocannula was retracted and the scleral and conjunctival incisionsclosed with 7-0 Vicryl suture. The subjects were observed and eyestissues recovered at 12 hours, 24 hours, 48 hours, 4 days, 7 days, 14days, 30 days and 90 days. Angiographic, histologic, and photographicstudies of the subjects demonstrated no sign of posterior segmentpathology. Recovered samples of choroid demonstrated significantconcentration of the drug, in the range of at least 1 mg per gram oftissue at all recovery time periods.

Example 7

A drug-containing formulation comprising 20 mL Healon 5 and 50 mL (1.5mg) bevacizumab (Avastin™, Genentech) was prepared. Eighteen porcinesubjects were anesthetized and the right eye prepared and draped in asterile manner. A conjunctival peritomy was made near the superiorlimbus, exposing and providing surgical access to a region of sclera. Asmall radial incision was made in the sclera, exposing bare choroid. Aflexible microcannula with a 360 micron diameter tip and 325 microndiameter body (iTrack microcannula, iScience Interventional Corp.) wasinserted in to the scleral incision and advanced in a posteriordirection to a target region behind the macula. The drug formulation wasinjected into the posterior region of the suprachoroidal space, and wasobserved to form a layer between the choroid and sclera at the targetregion. The microcannula was retracted and the scleral and conjunctivalincisions closed with 7-0 Vicryl suture. Another 18 porcine subjectswere anesthetized and each received a 50 mL bolus of bevacizumab viainjection into the vitreous. Both groups of test subjects were evaluatedand sacrificed at 0.5, 7, 30, 60, 90, and 120 days post-injection. Serumsamples were taken and tested for bevacizumab using an enzyme-basedimmunoassay. Higher plasma levels of bevacizumab were found in theintravitreally injected subjects and for longer duration of time thanthe suprachoroidal delivery group. The right globes were removed anddissected in order to quanitate bevacizumab in specific tissues andregions using an enzyme-based immunoassay. The enzyme immunoassaydemonstrated that bevacizumab delivered via intravitreal injection wasdistributed throughout eye, but when delivered suprachoroidally remainedlargely in the retina and choroid, with little found in the vitreous andanterior chamber.

Example 8

The experiment of Example 1 was repeated, except a drug formulation 0.2mL of Healon 5, 0.6 mL of Avastin, and 24 mg of triamcinolone acetonidewas prepared to provide a treatment with both anti-inflammatory andanti-VEGF properties. An approximately 5 mm long incision was madelongitudinally in the pars plana region transecting the sclera, exposingthe choroid of a cadaver globe that had been clarified by immersion inglycerol for approximately 30 minutes and perfused with saline at 12 mmHg pressure. The flexible microcannula of Example 6 was primed with thedrug formulation and the microcannula tip was inserted into thesuprachoroidal space through the scleral incision. With the aid of thefiber optic beacon at the microcannula tip, the distal end of themicrocannula was steered toward the posterior pole of the globe,stopping approximately 5 mm short of the optic nerve. Using aViscoelastic Injector (iScience Interventional), 70 microliters of thedrug formulation was injected into the posterior region of thesuprachoroidal space. The microcannula was removed by withdrawing thoughthe pars plana incision. The mixture was visible though the clarifiedsclera, and formed a deposit near the optic nerve with the mixture alsofollowing the catheter track. The incision was sealed with cyanoacrylate(Locktite 4011) and the globe perfused again with saline at 12 mm Hg for3 hours. The sclera was re-cleared by immersion in glycerol to examinethe administered drug formulation. The drug formulation was observed bymicroscopy to have formed a layer of dispersed drug within the polymerexcipient in the posterior region of the suprachoroidal space.

Example 9

A series of experiments were performed to evaluate minimally invasivedelivery of substances to the suprachoroidal space. The goal of theexperiments was to use non-invasive imaging and fluid dissection as ameans of delivering substances through scleral tissue and into thesuprachoroidal space, without having direct penetration into thesuprachoroidal space.

Human cadaver eyes were obtained from an eye bank and were prepared byinflating the eyes to approximately 20 mm Hg pressure with phosphatebuffered saline (PBS). A delivery needle was fabricated using stainlesssteel hypodermic tubing, 255 μm ID×355 μm OD. The needle distal tip wasground into a bi-faceted short bevel point, 400 um in length and at anangle of 50°. The fabricated needle was then silver-soldered into astandard 25 gauge×1 inch hypodermic needle to complete the assembly.

The needle was gently advanced into scleral tissue at an acute angle(<10°) with respect to the surface of the eye. The needle entry wasstarted in the pars plana region approximately 4 mm from the limbus, andthe needle advanced posteriorly in scleral tissue to create a tractbetween 5 and 6 mm long without penetrating through the sclera into thesuprachoroidal space. A high resolution ultrasound system (iUltrasound,iScience Surgical Corp.) was used to guide and verify placement of theneedle tip within scleral tissues and to document the injections.

In the first set of experiments, a polymeric excipient alone comprisinga hyaluronic acid surgical viscoelastic (Healon 5, Advanced MedicalOptics, Inc) was injected. In a second set of experiments, theviscoelastic was mixed in a 1:1 ratio with a 1% aqueous solution of 10micron diameter polystyrene microspheres (Duke Scientific, Inc) torepresent a model microparticulate drug. The viscoelastic and themixture were delivered through the needle using a screw driven syringe(ViscoInjector, iScience Surgical Corp.) in order to control deliveryvolume and injection pressure. The injections were made with the needlebevel turned inwards towards the center of the globe. Multiple locationson three cadaver eyes were used for the experiments.

In the first experiments, the needle tract was approximately 3 to 4 mmin length and the injectate was observed to flow back out the tract.With placement of the needle tip in a longer tract, higher injectionpressure was obtained and allowed the injectate to dissect through theremaining interposing layers of the sclera and deliver to thesuprachoroidal space. Through trials it was found that needle tipplacement in the outer layers of the sclera (<½ scleral thickness)resulted in the delivery of the viscoelastic into an intra-scleralpocket or sometimes through to the outer surface of the globe. With theneedle tip approaching the basement of the sclera, the injectionsdissected through the remaining interposing scleral tissue, entered thesuprachoroidal space and spread to fill the suprachoroidal space in theregion of the injection. FIG. 1 shows the needle tract 30 clearlyvisible (after removal of the needle) and a region 31 of thesuprachoroidal space filled with injectate. The sclera 1 and choroid 3are shown. FIG. 2 shows a region 33 of the suprachoroidal space filledwith the microsphere and hyaluronic acid excipient containing injectate,and the tip of the needle 4 in the sclera and needle shadow 32.

Example 10

An experiment was performed to use micro-endoscopic imaging to allowminimally invasive access to the suprachoroidal space in a human cadavereye. A custom fabricated, flexible micro-endoscope (Endoscopy SupportServices, Brewster N.Y.) with an outer diameter of 350 micronscontaining an imaging bundle with 1200 pixels was mounted on amicrometer adjusted stage. The stage was mounted on a vertical standallowing for controlled up and down travel of the endoscope. Themicro-endoscope was attached to a ½″ chip CCD camera and then to a videomonitor. A 20 gauge hypodermic needle was placed over the endoscope toprovide a means for piercing the tissues for access.

The camera was turned on and an external light source with a light pipe(Model MI-150, Dolan Jenner, Boxborough, Mass.) was used to providetranscleral imaging illumination. The needle was advanced until thedistal tip was in contact with the scleral surface of a human cadaverwhole globe approximately 4 mm posterior of the limbus. Themicro-endoscope was then lowered until the white scleral surface couldbe seen through the end of the needle. The needle was then slowlyadvanced into the scleral tissue by slight back-and-forth rotation. Asthe needle was advanced in this manner, the endoscope was lowered tofollow the tract created by the needle. At or within the sclera, theendoscopic image was seen as white or whitish-grey. As the needlepierced the scleral tissues, the image color changed to dark brownindicating the presence of the dark choroidal tissues, demonstratingsurgical access of the suprachoroidal space.

Example 11

An experiment was performed to use fiber-optic illuminated guidance toallow minimally invasive access to the suprachoroidal space in a humancadaver eye. A flexible microcannula with an illuminated distal tip(iTrack-250A, iScience Interventional, Menlo Park, Calif.) was placedinto a 25 gauge hypodermic needle. The microcannula comprised a plasticoptical fiber that allowed for illumination of the distal tip. Themicrocatheter fiber connector was attached to a 635 nm (red) laser diodefiber optic illuminator (iLumin, iScience Interventional) and theilluminator turned on to provide a steady red light emanating for themicrocannula tip. The microcannula was fed through the 25 gauge needleup to the distal bevel of the needle but not beyond.

The needle was slowly advanced in the pars plana region of a humancadaver whole globe until the needle tip was sufficiently embedded inthe scleral tissues to allow a slight advancement of the microcannula.The illumination from the microcannula tip was seen clearly as thescleral tissues diffused the light to a significant extent. As theneedle was advanced slowly, the microcannula was pushed forward at thesame time. When the hypodermic needle tip pierced through sufficientscleral tissue to reach the suprachoroidal space, the red light of themicrocannula tip immediately dimmed as the illuminated tip passed out ofthe diffusional scleral tissues and into the space beneath. Themicrocannula was advanced while keeping the needle stationary, therebyplacing the microcannula tip into the suprachoroidal space. Furtheradvancement of the microcannula in a posterior direction in thesuprachoroidal space could be seen transclerally as a focal red spotwithout the broad light diffusion seen when the tip was inside thescleral tissues. Using a high frequency ultrasound system (iUltraSound,iScience Interventional), the location of the microcannula in thesuprachoroidal space was confirmed.

What is claimed is:
 1. A drug formulation characterized by a zero shearviscosity of at least 300,000 mPas for injection into the suprachoroidalspace of an eye comprising a biologically active substance and athixotropic polymeric excipient that acts as a gel-like material tospread after injection and uniformly distribute and localize the drug ina region of the suprachoroidal space.
 2. The drug formulation accordingto claim 1 further characterized by a viscosity of not more than about400 mPas at 1000 s⁻¹ shear rate.
 3. The drug formulation according toclaim 1 wherein said gel-like material crosslinks after injection intothe suprachoroidal space.
 4. The drug formulation according to claim 1wherein said biologically active substance comprises microparticles ormicrospheres.
 5. The drug formulation according to any one of claims 1to 4 wherein said polymeric excipient comprises hyaluronic acid,chondroitin sulfate, gelatin, polyhydroxyethylmethacrylate, dermatinsulfate, polyethylene oxide, polyethylene glycol, polypropylene oxide,polypropylene glycol, alginate, starch derivatives, a water solublechitin derivative, a water soluble cellulose derivative orpolyvinylpyrollidone.
 6. A drug formulation for delivery to thesuprachoroidal space of an eye comprising a biologically activesubstance and microspheres or microparticles with an outer diameter inthe range of about 1 to 33 microns
 7. The drug formulation according toclaim 6 further comprising a polymer excipient to uniformly dispersesaid microspheres or microparticles in the suprachoroidal space.
 8. Thedrug formulation according claim 4 or 6 wherein the microparticles ormicrospheres additionally comprise a controlled release coating.
 9. Thedrug formulation according to claim 4 or 6 wherein the microparticles ormicrospheres additionally comprise a tissue affinity surface.
 10. Thedrug formulation according to any of claim 1 to 4 or 6 wherein thebiologically active substance comprises an antibiotic, a steroid, anon-steroidal anti-inflammatory agent, a neuroprotectant, an anti-VEGFagent, or a neovascularization suppressant.
 11. The drug formulation ofclaim 10 wherein the biologically active substance comprises both asteroid and an anti-VEGF agent or neovascular suppressant.
 12. A methodfor administering drugs to eye comprising placing formulation comprisinga biologically active substance and a polymer excipient in thesuprachoroidal space such that said excipient gels after delivery tolocalize said biologically active substance.
 13. The method according toclaim 12 wherein said formulation is placed in a posterior region of thesuprachoroidal space.
 14. The method according to claim 12 wherein saidformulation is placed in an anterior region of the suprachoroidal space.15. A method for administering drugs to a posterior region of the eyecomprising placing a formulation comprising a biologically activesubstance comprising microspheres or microparticles with an outerdiameter in the range of about 1 to 33 microns in an anterior region ofthe suprachoroidal space such that said microspheres or microparticlessubsequently migrate to said posterior region.
 16. The method accordingto claim 15 wherein said formulation comprises a polymer excipient touniformly disperse the microparticles or microspheres in thesuprachoroidal space.
 17. A method of administering drugs in thesuprachoroidal space of the eye comprising the steps of placing a needlein scleral tissues toward the suprachoroidal space at a depth of atleast half of the scleral thickness, and injecting a drug formulationthrough said needle into the sclera such that said formulation dissectsthe scleral tissues adjacent to said suprachoroidal space and enterssaid suprachoroidal space.
 18. The method according to any of claims 12to 17 wherein said formulation comprises a thixotropic polymer.